NO781884L - COMPOUNDS FROM THE PREGNAN RANGE WITH 19-PLACED OXYGEN FUNCTION, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

Compounds from the pregnane series with a 19-positioned oxygen function, methods for their preparation

position and pharmaceutical preparations containing these compounds.

The object of the invention is primarily pharmaceutical preparations containing at least one steroid compound from the pregnane series and with the formula:

1 2

wherein R means a hydrogen atom and R means an a-oriented lower

1 2

alkanoylthio group, or R and R together mean a carbon-carbon bond or an a- or 3-oriented methylene residue, R 3 means a free or with a lower alkyl etherified or with a lower alkanoyl esterified hydroxymethyl group, a formyl group, a carboxyl group or a lower alkoxycarbonyl group, and R<4> means a hydrogen atom or the acyl residue of a carboxylic acid Ac, and/or a corresponding salt and/or a 1,2-dehydro derivative thereof. The subject of the invention is also the method for producing these preparations, as well as the therapeutic use of these compounds and preparations in warm-blooded animals, especially humans.

The pharmaceutical preparations according to the invention are distinguished by favorable biological properties. In particular, they have a strong aldosterone-antagonistic effect, reducing the excessive sodium retention and potassium excretion caused by aldosterone. Therefore, as potassium-sparing diuretics, they find an important application in the therapy of diseases that are followed by disturbed mineral-water balance, e.g. in the treatment of heart insufficiency, rhythm disturbance due to potassium deficiency, in Cor pulmonale, liver cirrhosis, Ascites-Prophylaxe, diabetes mellitus and Hypertonie.

As steroids with aldosterone-antagonizing action, there are spiroxane derivatives to date, cf. e.g. Fieser and Fieser: Steroids, page 708, (Reinhold Publ. Corp., New York, 1959) and British Patent No. 1,041,534. Analogously active corresponding 173-hydroxy-21-carboxylic acids and their salts are also known, cf. e.g. US Patent 3,849,404. Compounds of this type used up to now in therapy have, however, a considerable disadvantage, in that they have a certain sex-specific activity which is affected by the usual long-term therapy sooner or later. Disturbances that are attributable to the antiandrogenic effect of the known antialdosterone preparations are particularly undesirable.

The. is also commonly known that 21-hydroxy-pregn-4-ene-3,20-dione (desoxycorticosterone) and its 21-esters which all have an analogous basic structure (4,5-unsaturated 3-ketone, hydroxyacetyl side chain) as the compound according to the invention, has an aldosterone-like physiological effect, i.e. in particular sodium retention and potassium excretion. Aldosterone itself also has this characteristic structural feature. Physiological effects of the same type were also established with 19-hydroxydeoxycorticosterone (19,20-dihydroxy-pregn-4-ene-3,20-dione), however, it only amounted to approx. 4% of the activity of 19-unsubstituted element (desoxycorticosterone), cf. J. Org. Chem. 31, 2427 (1954). In the case of other known 19-oxygenated analogues of desoxycorticosterone such as those with 10-acetoxymethyl-, 103-formyl- or 103-carboxyl group, no biological effect was mentioned; these compounds were only used as intermediates.

Likewise as intermediate products, resp. starting substances without any biological effect, some of some compounds of the type characterized by formula I were proposed. Thus, in the description in US patent no. 3,250,792 the compound was mentioned

12 3

with formula I, in which R and R together form a C-C bond, R means a hydroxymethyl or formyl group and R 4 means an acyl, as possible intermediates for corresponding 19-norsteroids. As starting materials for direct transfer into corresponding 19-norsteroids, compounds of formula I were proposed, in which R 1 and R 2 together form a C-C bond, R 3 means the formyl group and R 4 hydrogen or

acyl in the German Offenlegungsschrift 2,014,244. In US Patent No. 3,849,402, a general formula of a steroid 4,6-

diene, under whose numerous meanings of the substituents in 10"3-

and 173-position is also to find those which would correspond to the individual features of the compounds with the above-mentioned formula I, e.g. where R"^

and R 2 together form a C-C bond or R 3 means a hydroxymethyl group which can also be etherified with lower alkyl or esterified with an acetyl-, trialkylacetyl-, monohaloacetyl-

or trihaloacetyl residue, or R 4 means one of these acetyl residues. However, these structural elements were not combined so that

those in a narrower or more special selection would concern one of the compounds of formula I. A similar application for analogously characterized starting material can also be found in DOS 2,455,272, here, however, among starting materials for building up the cardenolide lactone ring, specifically 19-acetoxy-21 was proposed -hydroxy-pregna-4,6-diene-3,20-dione, however, it lacks any refer-

ning with regard to origin or manufacturing method, as well as physical data for the substance. In none of these four patents is there any mention of a biological effect or hint of a pharmaceutical application.

In the case of biological examination in the dose range of approx.

5-50 mg/kg, it was now found that the 19-oxygenated compounds of the above-mentioned characteristic formula I surprisingly have a distinct aldosterone-antagonizing effect, the undesirable side effect on the sex hormone household that is observed with the previous antialdosterone preparations, practically does not appear. Thus out-

folder e.g. 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate and -19,21-diacetate, as well as 7a-acetylthio-19,21-dihydroxy-pregn-4-ene-3, 20-dione-19-acetate a clear aldosterone-antagonizing effect at approx. 5 mg/kg peroral (Kagawa test with adrenalectomized male rats), whereas a detectable anti-androgen effect is still missing at doses above 50 mg/kg peroral (castrated male rats treated with testosterone propionate). With 19,21-dihydroxy-pregna-4,6-diene-3,20-dione, the average antialdosterone-effective dose is approx. 5 mg/kg, as no sex-specific side effect could be detected, e.g. such according to the said test on castrated rats, even after three times peroral administration of doses of 60 mg/kg each time.

Among the pharmaceutical preparations according to the invention

is to highlight those that contain at least one compound of formula I,

12 3

wherein R and R have the above meaning, R means a free or lower alkanoyl esterified hydroxymethyl group and R<4> means hydrogen or acyl, preferably those which are 1,2-saturated.

Particularly preferred are such preparations as at least

1 2 contains a 1,2-saturated compound of formula I, in which R and R together mean a carbon-carbon bond, R 3 means a hydroxymethyl or lower alkanoyloxymethyl group and R<4> means hydrogen or lower alkanoyl, above all however such, in which R 3 means a hydroxymethyl group and R<4> means hydrogen, or R^ is a lower-alkanoyloxymethyl group and R 4 is lower alkanoyl, lower alkanoyl residues derived from linear lower alkanoic acids being particularly preferred. Specifically, preparations containing 19,21-dihydroxy-pregna-4,6-diene-3,20-dione, its 19-acetate, 21-acetate or 19,21-diacetate should be mentioned.

Particularly preferred are also preparations containing at least one 1,2-saturated compound of formula I, in which R<1>means

2 3

hydrogen, R means α-acetylthio, R means hydroxymethyl, lower alkanoyloxymethyl, especially acetoxymethyl, or lower alkoxycarbonyl, especially methoxycarbonyl, and R 4 means hydrogen or lower alkanoyl, especially acetyl, above all those containing 7a-acetylthio-19,21-dihydroxy- pregn-4-ene-3,20-dione, its 19-acetate, 21-acetate or 19,21-diacetate.

Particularly preferred are also preparations containing at least one 1,2-saturated compound of formula I, in which R"<1>"

and R 2 together means an f^-positioned methylene group, R 3 means hydroxymethyl, lower alkanoyloxymethyl, especially acetoxymethyl, lower alkoxycarbonyl, especially methoxycarbonyl, and R<4> means hydrogen or lower alkanoyl, especially acetyl, above all those containing 19,21- dihydroxy-6B,7B-methylene-pregn-4-ene-3,20-dione, its 19-acetate, 21-acetate or 19,21-diacetate.

Generally, those preparations are preferred which contain at least one of the compounds of formula Ia which are particularly highlighted further below.

The object of the invention is also a process for the production of 19-oxygenated steroids of the pregnane series of the initially characterized formula I, especially of compounds of formula Ia:

in which R means a hydrogen atom and R an a-i' oriented lower alkanoylthio group or R 1 and R 2 together mean a carbon-carbon bond or an a- or 6-oriented methylene residue, Ra^ 3 means a free or with a lower alkyl ether or with a lower alkanoyl esterified hydroxymethyl group, a carboxyl group or a lower alkoxycarbonyl group and R<4>. means a hydrogen atom or the acyl residue of a carboxylic acid Ac, as well as of corresponding salts and 1,2-dehydroderivatives, as well as these compounds themselves including the salts and 1,2-dehydroderivatives. Hereby, it is to highlight compounds of formula Ia, including corresponding 1,2-dehydroderivatives, in which R 1 , R 2 , R 3 and R 4 have the above-mentioned meanings, with a 12 the•proportional rule that in 1,2-saturated compounds, in which R and R mean a C-C bond and R4 means an acyl residue Ac, R3 means a hydroxymethyl group etherified with a lower alkyl or esterified with a lower alkanoyl group, a carboxyl group or a lower alkoxycarbonyl group, and in 1,2-saturated compounds, in which R 1 and R 2 means a C-C bond and R<4>means hydrogen, R<a>3 means a free or preferably one with a lower alkyl etherified or esterified with a lower alkanoyl different from acetyl hydroxymethyl group, a carboxyl group, or a lower alkoxycarbonyl. Among these compounds are preferably 1,2-saturated compounds of formula Ia, in which R 1 and R 2 have the above meaning, R a3 means a free or lower alkanoyl esterified hydroxymethyl group and R means hydrogen or acyl Ac, especially with the for-1 2

general rule that in compounds, in which R and R together form a C-C bond and R<4> means an acyl radical Ac, R3 is a lower alkanoyloxy-12 4 methyl radical, and in which R and R together form a C-C bond and R means a hydrogen atom , R a3 is free or with a lower alkanoyl esterified hydroxymethyl group different from acetyl.

Particularly preferred are compounds of formula Ia, 1 2 12 in which R means hydrogen, and R means α-acetylthio or R and R together form a 3-oriented methylene group, R α3 means hydroxymethyl, lower alkanoyloxymethyl. or lower alkoxycarbonyl, especially methoxycarbonyl, and R<4> means hydrogen or lower alkanoyl, the lower alkanoyl residues in the symbols R S3 L and R 4 especially being linear lower alkanoyl residues, above all acetyl.

Particularly preferred are also compounds of formula IA:

in which R1 A means a lower akanoyl residue and Ra 2 means an acyl residue Ac, or Ra is a lower alkanoyl residue different from acetyl and

2 12

RA a hydrogen atom or R^ and R^ each means a hydrogen atom, as an acyl residue Ac is preferred a lower alkanoyl residue, and among lower alkanoyl residues linear lower alkanoyl residues, especially the acetyl residue is particularly preferred. Of particular note are 19,21-dihydroxy-pregna-4,6-diene-3,20-dione and 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19,21-diacetate, as well as all the compounds of formula I mentioned in the examples, resp. Yes.

Unless otherwise indicated, the term "lower" used in connection with the definition of a compound or a substituent refers to a compound or a substituent containing not more than 4 carbon atoms.

In the above-mentioned formula I, the acyl residue Ac derives from the carboxylic acids common in steroid chemistry, e.g. from aliphatic monocarboxylic acids with 1-8 C atoms, such as valerian, isovaleric, trimethylacetic, hexane, 2 2-dimethylbutyric and heptanoic acids, and especially from linear or branched lower alkanoic acids, such as formic acid, propionic acid, butyric acid, isobutyric acid and above all acetic acid. However, you can also use acids that are unsaturated and/or are substituted in the usual way, e.g. phenyl- and cyclohexylacetic acid, phenoxyacetic acid, B-cyclopentylpropionic acid, haloacetic acid, such as chloroacetic acid and trifluoroacetic acid, amino-acetic acid, a- or B-oxypropionic acid, benzoic acid and aliphatic dicarboxylic acids such as succinic acid and glutaric acid, or phthalic acid, whose other carboxyl group may be present as a salt, f .ex. with an alkali metal such as potassium or sodium.

A lower alkanoylthio group derives from the mentioned lower alkanoic acids, above all it is the acetylthio group.

A lower alkyl residue is preferably one with a straight carbon chain, e.g. ethyl, propyl, butyl and especially methyl. Preferred lower coco acid residues correspond to the aforementioned preferred lower alkyl residues, particularly preferred is the methoxy acid residue.

Those of the compound according to the invention which contain

holding a free carboxyl group, can, as already mentioned, also exist in the form of their salts. As salts, metal and ammonium salts in particular, such as alkali metal and alkaline earth metal, for example sodium, calcium, magnesium and preferably potassium salts, resp. ammonium salt derived from ammonia or a suitable, preferably physiologically tolerable, organic nitrogenous base. As a base, amines as well as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, di-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines, e.g. dicyclohexylamine, or benzyl amines, e.g. benzylamine and N,N1 ^.dibenzylethylenediamine, as also nitrogen-containing heterocyclic compounds, e.g. those of an aromatic character such as pyridine or quinoline, or those with an at least partially saturated heterocyclic ring, such as N-ethylpiperidine, morpholine, piperazine or N,N<*->dimethylpiperazine. ;The methods for preparing the compounds.with the above formulas. In resp.. Ia, as well as of corresponding salts and 1,2-dehydroderivatives are in and of themselves known as common methods in steroid chemistry. ;Compounds of formula I are obtained when a corresponding compound of the 17a-pregnan series with formula II: ; 12 3 4 ; in which R , R , R and R have the above meaning, are isomerized, as they are treated with an enolizing agent in An enolizing agent is, for example, a strong base, such as a quaternary organic hydroxide, e.g. tetraethylammonium hydroxide or N,N-dimethylpiperidinium hydroxy, or a hydroxide or alcoholate, such as a phenoxide or lower alkoxide, an alkali or alkaline earth metal, especially of sodium or potassium, such as especially potassium or sodium hydroxide, sodium methoxide and -ethoxide, and potassium -tert.-butoxide, but also potassium and sodium carbonate. An enolizing agent is in particular also a strong acid, e.g. a protic acid, such as a hydrohalic acid, especially hydrogen chloride and hydrogen bromide, further sulfuric acid, perchloric acid, or an organic sulphonic acid, e.g. benzenesulfonic acid, p-toluenesulfonic acid or p-bromosulfonic acid, but also a Lewis acid, such as boron trifluoride, or boron trifluoride etherate, pyridinium chloride, etc., as well as a medium-strong carboxylic acid, such as oxalic acid, formic acid or thioacetic acid. The isomerization is carried out in a manner known per se, usually in an organic solvent under anhydrous conditions. Any ester bonds present in the molecule, such as acyloxy and alkoxycarbonyl groups, can thereby be dissolved, to prevent this one can preferably work; with a catalytic amount of the enolizing agent and in. an arptic, especially anhydrous environment. The starting materials with formula II are available by production methods known per se, e.g. by breaking down the 17a-(2-hydroxyacetyl) side chain starting from corresponding 17-oxo compounds. of the further formula III indicated below, e.g. over 17a-cyano- and 17a-formyl- resp. 17a-carboxy compounds, in the manner described below for 173-isomers. ;Compounds of formula I are also obtained when in a corresponding 17-oxb compound of formula III: ; 12 3 ; in which R , R and R have the above meaning, the optionally acylated (2-hydroxyacetyl) side chain is introduced. The introduction of the hydroxyacetyl side chain takes place on i and. known manner. "-' E.g. by the stepwise build-up over the corresponding 17B-cyano compounds. These are available from 17-oxo compounds, e.g. by adding hydrogen cyanide to the 17-oxo group, the resulting mixture of epimeric 17- cyanohydrins to a 16,17-unsaturated 17-cyano compound and saturates the double bond by catalytic hydrogenation Alternatively, according to the method published in Tetrahedron 31, 2151 and 2157 (1975) by addition of tosylmethyl isocyanide (Ts-CH2-N=C) to the 17-oxo compound in the presence of a strong base directly forms the 17-cyano compound. This can, according to a variant, be hydrolyzed to the corresponding 17-carboxylic acid, which then in the form of the corresponding acid chloride with diazomethane gives the corresponding diazoketone (a 21-diazo-20- oxo compound) which on treatment with a carboxylic acid of the formula AcOH, in which Ac has the above-mentioned meaning, especially with acetic acid, gives the desired end product of the formula I. In another variant, one can primarily reduce 17-cyanophore the bond, e.g. according to one in J.Org.Chem. 3.5, 858 (1970) and J. Org. Chem. 29, 3046 (1964) mentioned method with diisobutylaluminum hydride of formula /"(CH^) 2CHCH2J72A1H to a corresponding 17-formyl compound (17-carboxaldehyde). (This is alternatively also available from the 17-oxo compound by reaction according to^ Wittig with methoxymethylenetriphenylphosphorane and by acid-catalyzed hydrolysis of the intermediate 17-methoxymethyl compound). The 17-formyl compound can then, for example, be reacted with a reagent that arises from formaldehyde-dimethylmercaptal-S-oxide (CH^-S-Cf^-SO-CH-j) by metallation with an organo-alkali metal compound, such as in particular with butyllithium. The intermediate product ; formed by the aldehyde group protected 20-hydroxy-21-aldehyde with partial formula: ; is hydrolyzed to the desired compound. with formula I under acid catalysis with simultaneous isomerization of the oxygen functions The hydrolysis is carried out under the usual conditions for acid hydrolysis, for example with an aqueous inorganic acid, such as hydrochloric acid, in a water-miscible organic solvent, possibly knead at an elevated temperature until the boiling temperature of the reaction mixture. The usual desulphurisation agents such as cadmium and mercury salts are not necessary for the hydrolysis. In particular, the non-participating oxygen-containing functional groups above all the oxo groups, such as the 3-oxo group in particular, are protected during the above-mentioned reactions transiently in the usual way, for the protection of the 3-oxo group it is advantageous thioketalization, e.g. with ethylenedithiol. The 17-oxo compounds of formula III used as starting materials are mostly known or, if they are unknown, available analogously to the known compounds by known production methods. ;1 2 ;Compounds in which R and R together form a C-C bond, as well as their 1,2-dehydroderivatives can also be obtained according to a general method, the corresponding 6,7-saturated starting material with formula IV in which R 3 and R 4 has the above meaning, resp. a 1,2-dehydro derivative, or a 3-enoleter of 1,2-saturated compounds, is dehydrated in the 6,7-position and possibly also in the 1,2-position at the same time, with the 3-ether group possibly present being split . The 6'y7-dehydration takes place according to methods known per se, for example by treatment with a dehydrating quinone, e.g. chloranil and especially 2,3-dichloro-5,6-dicyan-1,4-benzoquinone. When using the first, one preferably works at boiling heat in organic solvents, e.g. aromatic hydrocarbons, such as benzene or xylene, lower aliphatic alcohols, such as ethanbl, propanol or tert-butyl alcohol, lower aliphatic ketones, such as a: etone or 2-butanone, aliphatic esters, such as acetic esters or cyclic ethers, such as dioxane or tetrahydrofuran. When using dichlorodicyanobenzoquinone, one preferably works in the presence of hydrochloric acid at or below room temperature in a water-miscible organic solvent, e.g. one of the above. In an analogous way, one can also convert a corresponding 3-enol ether, preferably a lower alkyl, such as methyl or ethyl enol ether, or also hydrogenate under the influence of manganese dioxide, preferably in a halogenated hydrocarbon, such as chloroform or dichloromethane, to the desired end product, as the ether-forming residue is split off. The 3-ether to be used can be obtained by usual known methods, preferably by treating a corresponding 4,5-unsaturated-3-ketone with a corresponding formic acid orthoester, such as methyl orthoformate or ethyl orthoformate under acid catalysis. The possibly carried out simultaneous 1,2- and 6,7-dehydrogenation of the 1,2-saturated 4-en-3-one compounds or their 3-enols also takes place in a manner known per se by treatment with a dehydrating quinone, above all 2,3-diclo-5,6-dicyan-1,4-benzoquinone. Preferably, the latter reaction agent is allowed to take effect at boiling heat for several, e.g. 6-24 hours, - as up -solvent, the same organic solvent can be used as was mentioned above for the chloranil dehydration. ;Starting substances with formula IV are known or available by processes known per se in an analogous way.. ;6>7-unsaturated compounds with formula I, in which R;2 3 ;together with R means a C-C bond, R a lower alkanoyloxymethyl group and R 4 an acyl group.Ac, can also be prepared as the corresponding 6 6,19 epoxide with formula V: ; ; in which R 4 has the above meaning, according to the method'according to German patent no. 1,196,651 reacts with an acylating agent derived from a lower alkanoic acid in an anhydrous m edium in the presence of a strongly acidic catalyst. The acylating agent can be the acid itself, such as formic acid, or preferably a reactive derivative of lower alkanoic acids is used, such as an anhydride and especially a symmetrical anhydride. A strongly acidic catalyst is preferably an oxygen-containing acid, such as sulfuric acid, perchloric acid or an organic sulphonic acid, e.g. p-toluenesulfonic acid, p-bromobenzenesulfonic acid or benzenesulfonic acid; as a solvent you can use lower alkanoic acids, especially those that correspond to the acylating agent, you can also work in aprotic solvents, e.g. hydrocarbons, especially aromatic hydrocarbons such as benzene or toluene, or in halogenated aliphatic hydrocarbons such as especially chloroform and methylene chloride, with advantage when working with temperatures of approx. 0°C up to the boiling point of the reaction mixture, preferably at room temperature. When a starting material of formula V, in which R 4 is a hydrogen atom, is converted, this is simultaneously exchanged for the acyl residue of the acylating agent. The starting substances of formula V are known or obtainable by known analogue methods. The compounds of formula I are also obtainable, in that in a corresponding derivative with a protected, especially ketalized or thioketalized 3- and/or 20-oxo group, protective groups are removed. or groups during liberation of the oxo group or groups. ;As derivative.-'with. protected 3-oxo group, 3-ketals and especially 3-thioketals come into consideration. As 3-ketals, they are preferred as derived from lower alkanols, such as methanol or ethanol, and especially from α- or 3-glycols such as 1,2- or 1,3-propanediol > 1,2- or 2,3-butanediol , and above all ethylene glycol. As 3-thioketals, those derived from sulfur analogues of already mentioned glycols come into consideration in particular, particularly preferred are 3,3-ethylenedithio derivatives. Thioketals and especially ketals of the above type are suitable for protecting the 20-oxo group. The removal of these protective groups takes place in a manner known per se by hydrolysis, preferably under the general conditions for acid catalysis. In the case of thioketals, however, one preferably works with the addition of a sulphur-binding compound, e.g. a metal salt, especially a heavy metal salt, such as cadmium carbonate and/or mercury(II) chloride. As the latter agent reacts strongly acidic even in the presence of water, no additional acid is required as a catalyst when using it. If desired, the compounds formed within the scope of the above-mentioned final substances can be converted into each other. 1 2 6,7-dehydro compounds of formula I, in which R and R together form a C-C bond, can, when desired, by addition of a lower alkanethioic acid be converted into the corresponding 1 2 ;end substances, in which R means a hydrogen atom and R means an α-oriented lower alkanoylthio group. The deposition takes place in a manner known per se, preferably heating the 6,7-dehydro compound in question in excess thiocarboxylic acid (lower alkyl cyano acid), possibly under irradiation with ultraviolet light. Usually, the reaction proceeds with sufficient speed at temperatures all slightly above room temperature, such as e.g. at approx. 50°C, therefore it is advantageous in the case of lower boiling thiocarboxylic acids, e.g. especially thioacetic acid to react at boiling heat, with higher-boiling thiocarboxylic acids, on the other hand, to keep the reaction temperature at approx. 90-100°C, - the required reaction times can extend up to several hours, however, ensures a sufficient turnover under mild conditions. In a typical method, the formed product crystallizes directly after cooling, possibly after previous evaporation of excess reactant, if desired, however, the product can also be isolated or cleaned in the usual way, e.g. by chromatography. With this addition, predominantly a single isomer occurs, which due to the analogy with other known similar compounds is attributed to the above-mentioned structure (R is hydrogen, R 2 is one α-positioned lower alkanoylthio group) according to what is known today. The material basis for the description which refers to a product of this type shall, however, remain valid in the event of a random subsequent assignment to another structure. ;6,7-dehydro compounds of formula I, in which R 1 and R<2> together form a C-C bond can, if desired, be converted by adding a methylene group to the corresponding end substances, in which ;1 2 ;R and R together mean 6a ,7- or especially the 63,7-methylene group. Preparation takes place according to methods known per se, of which a preferred variant is, however, to mention the one in which a corresponding above-mentioned 6,7-dehydro compound is reacted with dimethyloxosulfonium methylide. This variant also has the significant advantage that, in the case of compounds with free 19-hydroxyl groups, it has a very high stereospecificity and predominantly gives 6,7-methylene compounds with the preferred 3-configuration of the methylene group. The reaction is suitably carried out by combining under an inert gas, such as in a nitrogen atmosphere and with the exclusion of moisture, a mineral oil dispersion of sodium hydride with trimethylsulfoxonium iodide and adding dimethylsulfoxide, whereupon the formation of dimethyloxosulfonium methylide takes place. For this in situ produced reagent, 6,7-unsaturated steroid starting material in molar ratio (reagent:steroid) from approx. 1:1 to 5:1. The reaction is allowed to take place at approximately room temperature and the reaction mixture is treated with water, after which the steroid is isolated using usual methods. ;In the case of such final substances, which contain alkali-sensitive groups such as ester groups, the cleavage of the reaction mixture is appropriate and thus leads to the pH remaining as much as possible in the neutral or slightly acidic range., ;One can also dehydrate 1,2-saturated compounds to the corresponding 1,2-dehydroderivatives in a manner known per se.' To this end, biological dehydration methods can be used, e.g. by means of the microorganisms Corynebacterium simplex or Septomyxa affinis or treat their enzyme systems dehydratingly, or with selenium dioxide in an organic solvent, e.g. tert-butyl alcohol. However, it is preferably reacted with 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, e.g. as discussed above for the simultaneous 1,2- and 6,7-dehydration. Compounds with a free carboxyl group can be converted into the corresponding salts in a manner known per se, by treating them with a base, e.g. ammonia, an alkali or alkaline earth base or an organic base, e.g. one of the above, when a free acid is desired, this is released by acidifying a salt. As alkali or alkaline earth bases are used e.g. corresponding hydroxides, such as sodium and especially potassium hydroxide, carbonates, such as sodium and potassium carbonate, or hydrogen carbonates such as sodium and potassium hydrogen carbonate. ;The 106-positioned oxygenated residue R 3 as well as the 21-positioned group OR 4 can, if desired, in compounds of formula I be converted into another residue within the scope of the definition of the symbols ;3 4 ;R resp. R, in particular a hydroxyl group can be esterified or etherified, or an esterified hydroxyl group is released, the 106-hydroxymethyl group is oxidized to a formyl group or also to a carboxyl group, as well as the formyl group to the carboxyl group, the carboxyl group is esterified, and an esterified carboxyl residue is released. All these transformations take place in a manner known per se and can also be carried out in appropriate combinations and - possibly under the usual "transient protection" of other functional groups present, such as in particular the 3- and/or 20-oxo group, as well as the 21-hydroxyl group. By the conventional protection of oxygen-containing functional groups is understood throughout the description the conversion of a hydroxyl group or carboxyl group in an esterified form, and an oxo group in an acetal or ketal, or in a thioacetal or thioketal, since both the introduction and the removal of the protective groups takes place in a generally known manner.. ;Ketalization and thioketalization are particularly taken into account as appropriate precautions for protecting the 20- and also 3-oxo groups. The reactions take place in a manner known per se, especially under the condition for acid catalysis and possibly using variine-attracting agents, or azeotropic distillation. n for example lower alkanols, such as methanol or ethanol and especially α- and 3-glycols, such as 1,2- or 1,3-propanediol and 1,2- or 2,3-butanediol, and above all ethylene glycol, or reactive derivatives of these alcohols, such as acetals or ketals, especially those in which the carbonyl components are easily volatile, such as e.g. 2,2-dimethyl-1,3-dioxolane. In an analogous way, but starting from sulfur analogues of the above-mentioned alcohols, above all from 1,2-ethanedithiol or a reactive derivative thereof, one arrives at analogous thioketals. The esterification or etherification which, if desired, is to be carried out by the hydroxyl group likewise takes place in a manner known per se. For esterification, one treats, for example, the compound to be esterified with excess acid itself, such as with formic acid or with a reactive derivative thereof, e.g. with a derivative or one of the above-mentioned acids, especially with an anhydride or acid halide, such as acid chloride, preferably in the presence of a tert. base such as pyridine, quinoline or N-ethyl-piperidine. For etherification, for example, the compounds to be etherified are treated with reactive derivatives of alcohols, e.g. with esters with strong acids such as halides, sulfates or sulfonic acid esters, where as alcohol components in particular a lower alkanol, such as methanol and ethanol in particular, comes into consideration. The subsequent liberation of the protected oxygen-containing functional groups takes place in a manner known per se by hydrolysis. Acetal and ketal groups are preferably hydrolysed under the usual conditions for acid catalysis. Thioacetals and thioketals are also hydrolysed in this way, preferably as stated above. ;Esterified hydroxyl groups, whether in an acylated hydroxyl group or an esterified carboxyl group, can also be hydrolysed under acidic conditions, preferably, however, they are hydrolyzed under base catalysis. As basic catalysts, hydroxides, carbonates or hydrogen carbonates of alkali metals or alkaline earth metals, especially of sodium or potassium. Since the 21-positioned hydroxyl group can be released under milder conditions of base-catalyzed hydrolysis than the 19-positioned hydroxyl group, it is possible to hydrolyze the esterified 21-hydroxyl group while retaining a similarly esterified 19-hydroxyl group selectively. Conversely, it is also possible with the use of a difficult-to-hydrolyse acyl residue, e.g. of the benzoyl residue to esterify the 21-hydroxyl group to achieve the selective release of the 19-hydroxyl group. "The esterification that may be carried out by the carboxyl group also takes place in a manner known per se." For example, the carboxylic acid to be esterified is treated with excess alcohol, especially one of the above, in the presence of a water-attracting agent, especially a symmetrically substituted carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or also an acidic catalyst, e.g. a strong inorganic acid, or one first transfers the free acid into a reactive derivative, such as chloride or anhydride, and reacts this with the desired alcohol. The ester according to the invention, above all methyl ester, can also advantageously be prepared by reacting a free carboxylic acid to be esterified with the corresponding diazolaveralkane, above all diazomethane. Where in the present description acid catalysis is mentioned without further specific indications, this is understood to mean treatment in the presence of an inorganic acid, e.g. sulfuric acid, perchloric acid or a hydrohalic acid, such as chloro, bromic or hydroiodic acid or especially an organic acid, e.g. a sulfonic acid such as p-toluenesulfonic acid in particular or a strong carboxylic acid such as oxalic acid or formic acid. The free 19-hydroxyl group of the 10B-hydroxymethyl group can also be oxidized in a manner known per se to the 19-oxo group of the 103-formyl group. The preferred oxidizing agent is therefore compounds of hexavalent chromium, such as chromium trioxide, chromic acid and their alkali metal salts, with lower alkane carboxylic acids such as acetic or propionic acid, or pyridine or acetone, optionally diluted with a halogenated lower alkane such as dichloromethane or chloroform, being used as the reaction medium. and keeps the reaction temperature preferably below room temperature. The hydroxymethyl group, or also the formyl group, can be oxidized with the mentioned chromium compounds further to the carboxyl residue, using extended reaction times, temperatures at or slightly above room temperature, (not above approx. 50°C) and/or aqueous sulfuric acid as a solvent for the oxidizing agent . To the compounds of formula I corresponding derivatives with a protected 3- and/or 20-oxo group can preferably be obtained starting from known 19,21-dihydroxypregn-4-en-3,20-dione- or 19-hydroxy-sy -androst-4-ene-3,17-dione compounds according to the general methods known above, in particular by modification of the group R<3> under protection of the oxo group. The invention also relates to the embodiments of the above-mentioned method, where one starts from a compound formed at one or other step as an intermediate and carries out the missing steps or where a starting material is formed under the reaction conditions. The pharmaceutical preparations according to the invention, which contain the compounds of formula I, can in particular be used for the treatment of hyperaldosteronism of various forms. They contain an effective amount of the active substance alone or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers and, if desired, also with other pharmacological or therapeutically valuable substances and are particularly suitable for enteral, e.g. oral or rectal, or for parenteral administration. The term "active substance" is meant in the following as a compound of formula I, as it is initially defined in the context of the pharmaceutical preparations according to the invention in the general and special specific meanings. The invention relates in particular to pharmaceutical compositions containing as active substance at least one of the compounds of formula I according to the invention (including 1,2-dehydroderivatives and salts) in the form of a sterile and/or isotonic aqueous solution, or also in a mixture with at least a solid or semi-solid carrier material. The invention also relates to pharmaceuticals and especially pharmaceuticals in the form of dosage units that contain at least one of the compounds according to the invention alone or in a mixture with one or more carriers, especially such in solid form. The invention particularly relates to medicinal products in the form of tablets (including lozenges, granules and lozenges), dragées, capsules, pills, ampoules, dry vials or suppositories containing at least one of the active substances of formula I alone or in admixture with one or more carriers. The term "drug" is used here to denote individual separate portions of uniform composition suitable for medical administration. The term "drug in the form of dosage units" is used here to denote individual separate portions of uniform composition which are suitable for medical administration and each individually contains a specific amount of the active substance according to the invention which roughly corresponds to 0.025 to approx. 4, preferably 0.1 to approx. 1 daily dose. 'Carriers' for use in pharmaceutical compositions (e.g. granules) for the production of tablets, dragées, capsules and pills are e.g. the following: a) diluent, e.g. starch, sugar, such as lactose, glucose and sucrose, mannitol, sorbitol and silicic acid, b) binder, e.g. carboxymethylcellulose and other cellulose derivatives, alginic acid and its salts, such as sodium alginate, gelatins and polyvinylpyrrolidone, c) moisture regulators, e.g. glycerol,;d) explosives, e.g. agar-agar, calcium carbonate and sodium bicarbonate, e) retarder to slow down the absorption of the active substance, e.g. paraffin, f) ' resorption accelerators e.g. quaternary ammonium compounds, g) ' surfactants f, e.g. cetyl alcohol and glycerol monostearate, ;h) adsorbent, e.g. kaolin and bentonite',;i) flow control and lubricant, e.g. talc, calcium stearate, magnesium stearate and solid polyethylene glycols. ;These and similar carrying resp. excipients can also serve several of the above purposes. The tablets, dragées, capsules and pills containing the above-mentioned pharmaceutical compositions according to the invention can be equipped with the usual coatings and sheath materials, to which, if desired, dyes or pigments are mixed, e.g. ;for identification or characterization purposes. These covers can also have such a composition that enables a delayed release of the active substance, for this purpose it is e.g. suitable waxes and cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. These compositions can also be processed in the form of microcapsules. Medicines for parenteral administration are preferably ampoules containing a single dose of the active substance according to the invention, especially a water-soluble physiologically tolerable salt in the form of an aqueous solution, which is preferably sterilized and optionally contains the usual buffering agents and/or neutral inorganic salts such as sodium chloride, as an aid for setting isotonicity with blood. Such an aqueous solution ... is also well suited for the production of injectable solid drug forms, such as dry vials, in which a quantity of the solution corresponding to the single dose is evaporated in the usual way, e.g. by lyophilization, and the solid residue only immediately before use with sterile water is brought into the form of the injection solution. As carriers for pharmaceutical compositions for administration into suppositories, it is suitable for common suppository base materials, e.g. natural or synthetic triglycerides such as cocoa butter, paraffin hydrocarbons, polyethylene glycols; and higher alkanols, gelatin rectal capsules containing as base material e.g. liquid triglyceride, polyethylene glycol or paraffin hydrocarbons. The pharmaceutical compositions according to the invention preferably contain from approx. 0.1 to 99.5, especially from approx. ;1 to approx. 90% by weight of the active substance. The recommended daily dose for a 75 kg human or warm-blooded animal is approx. 5-500 mg, preferably approx. 20-300 mg, it can, however, be varied within wide limits depending* on type, age and individual reactivity. The production of the above-mentioned pharmaceutical compositions, preparations, drugs and drugs in the form of dosage units takes place with the help of ordinary, in and of themselves known manufacturing methods for the pharmaceutical industry, e.g. by means of usual mixing, granulating, tableting, coating, dissolving and lyophilizing methods, with, if desired, working under germ-free conditions or sterilizing an intermediate product or a finished product.

The invention also relates to the use of the compounds of formula I to combat the various forms of Hyperaldosteronism in humans and other warm-blooded animals, as well as a corresponding therapeutic method, which is characterized by administering an effective dose of at least one of the active substances according to the invention alone, or together with one or more carriers, or in a medicinal form. The ..active substances according to the invention are thereby administered enterally, e.g. rectally or above all orally, or parenterally, such as intraperitoneally or intravenously.

The invention will be explained in more detail with the help of some examples, in which the temperature is indicated in degrees Celsius.

Example 1

A solution of 1.70 g of 19,21-dihydroxypregn-4-ene-3,20-dione-19,21-diacetate (Chem.Pharm.Bull (Tokyo) 6,325 (1958)) and 2.5 g of chloranil in 50 ml of methanol is heated for four hours under reflux, evaporated in vacuum to approximately one third and diluted with approx. 400 ml ethyl acetate. The solution is freed from solid impurities by filtration, washed with a saturated solution of sodium dithionite in N sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel; elution with a mixt

of hexane-ethyl acetate (3:1) gives purified 19,21-dihydroxypregna-4-diene-3,20-dione-diacetate, which is suitable for further processing

(j fr. Example 2).

Temp. 152-154°C (from methylene chloride-ether).

In an analogous way, starting from a corresponding 4,5-unsaturated 3-oxo compound, the following compounds can also be obtained: 19,21-dihydroxypregna-4,6-diene-3,20-dione, m.p. 161-164°C 19,21-dihydroxypregna-4,6-diene-3,20-dione-21-acetate, 19,21-dihydroxypregna-4,6-diene-3,20-dione-19-acetate-21 -benzoate, 19,21-dihydroxypregna-4,6-diene-3,20-dione-19,21-dibutyrate, amorphous, 19,21-dihydroxypregna-4,6-diene-3,20-dione-19- formate-21-benzoate, 21-hydroxy-19-methoxy-pregna-4,6-diene-3,20-dione-2l7acetate,

m.p. 159-161°C,

/o7D= + 176° (c = 0.5 chloroform),

21-hydroxy-3,20-dioxopregna-4,6-diene-19-acid and its acetate, butyrate and benzoate,

21-hydroxy-3,20-dioxopregna-4,6-diene-19-acid methyl ester and its acetate and propionate.

Example 2

A solution of 1.4 g of the 19,21-dihydroxypregna-4,6-diene-3,20-dione diacetate formed according to Example 1 in 80 ml of methanol is mixed with a solution of 1.0 g of sodium bicarbonate in 20 ml of water , stirred under an argon atmosphere for four hours at room temperature, and then evaporated in vacuo. The residue is distributed between methylene chloride and water, and the organic phase is washed with sodium chloride solution, dried with sodium sulphate and evaporated.

Chromatography on silica gel and elution with a mixture of hexane-ethyl acetate (1:1) gives 19,21-dihydroxypregna-4,6-diene-3,20-dione-19-acetate, which after redissolution from methylene chloride-iso-propyl ether melts at 100-103°C.

4

Example 3

A solution of 100 mg of 19,21-dihydroxypregna-4,6-diene-3,20-dione diacetate in 6.5 ml of methanol is mixed with a solution of 211 mg of sodium bicarbonate in 2.6 ml of water, heated to boiling for three hours under reflux and evaporated in vacuo. A solution of the residue in methylene chloride is washed with a 15% aqueous sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The residue is taken up in a mixture of hexane-ethyl acetate (1:1)

and chromatographed on silica gel. The product is redissolved after evaporation of the solvent from methylene chloride-diethyl ether-diisopropyl ether, whereby 19,21-dihydroxypregna-4,6-diene-3,20-dione is produced, m.p. 161-164°C.

Example 4

A solution of 500 mg of 19 ^l-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate in 14 ml of methanol and 0.8 ml of thioacetic acid is refluxed for one hour, cooled to room temperature and mixed with water to cloudiness. The reaction mixture is evaporated in vacuo to dryness at a maximum of 45°C and the residue is chromatographed over silica gel. Elution with a mixture of hexane-acetone (4:1) gives the chromatographically uniform 7α-acetylthio-19,21-dihydroxy-pregn-4-ene-3,20-dione-19-acetate, which on lyophilization from aqueous methanol ifaés in amorphous form. IR spectrum. (in methylene chloride): 3'460, 2950, 1740, 1690, 1670, 1625, 1385, 1365, 1355, 1335, 1230, 1120, 1080, 1040, < 955, 910 cm"<1>.

In an analogous way, 7a-acetylthio-21-hydroxy-19-methoxy-pregn-4-ene will be obtained from 21-hydroxy-19-methoxy-pregna-4>6-diene-3,20-dione-21-acetate 3,20-dione-21-acetate, amorphous (precipitated from aqueous methanol); /°l/d= + "78° (c = 0.5, chloroform), IR spectrum (imethylene chloride): 2950, 1745,. 1720, 1690, 1670, 1620, 1375, 1360, 1235, 1120, 1085, 965 cm<-1>.

Example 5

A solution of 0.6 g of 66,19-epoxy-21-hydroxy-pregn-4-ene-3,20-dione-21-acetate and 1.3 g of p-toluenesulfonic acid in 26 ml of methylene chloride and 5.2 ml of acetic anhydride stirred for 16 hours at 45°C and then poured onto an ice-cold solution of 13.5 g of sodium acetate in 130 ml of water with stirring. The aqueous layer is extracted after separation of the organic layer with ethyl acetate, the combined organic extracts are washed successively with water, aqueous sodium bicarbonate solution and water, dried and evaporated.

Crystallization of the crude product formed from methylene chloride-ether yields 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19,21-diacetate with m.p. 152-154°C.

In an analogous manner, however, using an equivalent amount of butyric anhydride, 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-butyrate-21-acetate is obtained.

Example 6

a) Under an argon atmosphere, a solution of potassium tert-butoxide is prepared from 34 g potassium and 980 ml tert-butanol, a solution of 45 g of 3,3-ethylenedithio-19-hydroxy-androsta-4,6-dien-17-one in 1000 ml of 1,2-dimethoxyethane at room temperature under an argon atmosphere is quickly added to this while stirring. - After stirring for 15 minutes, the reaction mixture is mixed during 90 minutes at 25°C with a solution of 35.5 g of tosylmethyl isocyanide in 1000 ml of 1,2-dimethoxyethane, stirred for a further hour and poured into ice water. The organic layer is separated, the aqueous layer is extracted with methylene chloride and the combined organic extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is chromatographed over a silica gel column, eluted with a mixture of hexane-ethyl acetate (4:1) and 24 g of 3,3-ethylene-dithio-173-cyano-androsta-4,6-dien-19-ol are obtained, m.p. 180-181°C after simple crystallization from methylene chloride-diisopropyl ether: /q/D= +162° (c = 0.14, chloroform). Further elution with the same solvent mixture gives 12 g of 3,3-ethylenedithio-17a-cyano-androsta-4,6-dien-19-ol, m.p. 211-213°C (from methylene chloride-ethyl acetate), /ot/D= 61° (c= 0.48, chloroform). b) A solution of 24 g of 3,3-ethylenedithio-173~cyano-androsta-4,6-dien-19-ol in 450 ml of 1,2-dimethoxyethane is mixed at -20°C dropwise over 15 minutes with 400 ml of a 20% solution of diisobutylaluminum hydride in toluene with stirring, is heated to 25°C and stirred at room temperature for a further hour. The reaction mixture is poured onto ice-water, acidified with hydrochloric acid, and stirred for one hour. The product is taken up in methylene chloride,

the organic phase is washed in sequence with water, aqueous sodium bicarbonate solution qg water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is chromatographed over a silica gel column, elution with a mixture of toluene-ethyl acetate (95:5) gives 3,3-ethylenedithio-19-hydroxy-androsta-4,6-diene-17$-carboxaldehyde, smp. 165-166°C (from methylene chloride-diisopropyl ether), /o7D= + 198° (c = 0.474, chloroform).

c) A solution of 6.7 ml of formaldehyde-dimethylthioacetal-S-oxide (methylthiomethyl-methyl-sulfoxide) in 80 ml of tetrahydrofuran

treated under an argon atmosphere at -20°C dropwise with 13.5 ml of a 1.6-molar solution of butyllithium in hexane, so that the temperature does not rise above -17°C. The reaction mixture is then mixed dropwise with a solution of 13 g of 3,3-ethylenedithio-19-hydroxy-androsta-4,6-diene-173-carboxaldehyde in 100 ml of tetrahydrofuran over 30 minutes and further stirred for 30 minutes. The reaction mixture is poured onto ice-water and the product is taken up in ethyl acetate.

The combined organic extracts are washed successively with water and

a saturated aqueous sodium chloride solution, dried over sodium sulfate, evaporated in a water jet vacuum and the residue applied to a silica gel column. By elution with a mixture of hexane-ethyl acetate (1:1) the unreacted starting material is regenerated, with a mixture of ethyl acetate-acetone (2:1) you elute fractions which, after evaporation, give a crystalline isomer mixture of 3,3-ethylene-dithio- 21£-methyl-sulfinyl-2l^-methylthio-pregna-4,6-diene-19,20^-diol, which is further processed without separation. d) A solution of 15.9 g of the isomer mixture formed according to point c) in 960 ml of acetone is mixed with 42 ml of water, 12 g of mercury (II) chloride and 12 g of cadmium carbonate, stirred for 5 hours at room temperature and filtered off through a layer of diatomaceous earth. The filter cake is extracted with methylene chloride, the extract is combined with the original filtrate and evaporated. The resulting crude mixture of isomeric 19,205-dihydroxy-21?-methylsulfinyl-21?-methylthio-pregna-4,6-dien-3-ones is further processed directly in the next step. e) The isomer mixture from step d) is dissolved in 300 ml of tetrahydrofuran, mixed with 50 ml of 5N hydrochloric acid and stirred for 13 hours

at room temperature. The reaction mixture is poured into 2 liters of ice water and the product is taken up in methylene chloride. The combined extracts are washed successively with a dilute sodium carbonate solution, water and a saturated sodium chloride solution, dried over sodium sulfate

and evaporated in a water jet vacuum. The residue is chromatographed over a silica gel column, elution with a mixture of hexane-acetone (2:1) yields 19,21-dihydroxy-pregna-4,6-diene-3,20-dione which, after crystallization from acetone-hexane, melts at 163-165°C and is identical to the product according to examples 1 and 3.

Example 7

A solution of 386 mg of 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate in 3 ml of pyridine is mixed with 1.5 ml of benzoyl chloride, left at room temperature for 30 minutes and poured on ice water. After stirring for 15 minutes, the reaction mixture is extracted with ethyl acetate, the organic phase is washed successively with a dilute sodium carbonate. solution, 1N hydrochloric acid and with water, dried over sodium sulphate and evaporated in a water jet vacuum. The resulting 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate-21-benzoate melts after redissolving from methylene chloride-diisopropyl ether at 120-121°C.

In an analogous way using the same amounts of weight

of starting and auxiliaries, the following esters of 19,21-dihydroxy-pregna-4,6-diene-3,20-dione are obtained: with propionic anhydride, the oily 19-acetate-21-propionate; IR spectrum (in methylene chloride) : 2950, 1740, 1725, 1615, 1365, 1225, 1180, 1080, 1035, 880 cm"<1>"

with valeric anhydride the oily 19-acetate-21-valerianate; IR spectrum (in methylene chloride): 2950, 1740, 1725, 1660, 1620, 1585, 1370, 1225, 1170, 1100, 1035, 880 cm<-1>, and

with pivaloyl chloride the oily 19-acetate-21-pivalate;

IR spectrum (in methylene chloride): 2950, 1735, 1720, 1655, 1615, 1585, 1365, 1225, 1160, 1100, 1035, 890 cm"<1>.

Example 8

A solution of 300 mg of that according to example 7

formed 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate-21-pivalate in 18 ml of methanol is mixed with a solution of 180 mg

. sodium bicarbonate in 3.6 ml of water, stir for 4 hours at 45°C

and evaporated in a water jet vacuum to dryness. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulphate and evaporated. Crystallization from methylene chloride-diisopropyl ether gives 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-21-pivalate, m.p. 173-174°C.

Example 9

A solution of 100 mg of 19,21-dihydroxy-17a-pregna-4,6-diene-3,20-dione-19,21-diacetate (obtainable by processing the 3,3-ethylenedithio-17a- mentioned in Example 6 cyano-androsta-4,6-dien-19-ol according to method steps b-e in Example 6) in 2.5 ml ethanol is mixed with 0.25 ml conc. hydrochloric acid and heated to reflux - for 30 minutes. The volatile parts of the reaction mixture are removed by evaporation in a water jet vacuum, the residue is dissolved in 1 ml of pyridine and treated with 0.5 ml of acetic anhydride. After standing for 17 hours at room temperature, the mixture is evaporated in vacuo, the residue is dissolved in ethyl acetate and washed successively with 1N hydrochloric acid, a dilute sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column, elution with a mixture of hexane-ethyl acetate-acetone (12:2:1) first gives a small flow of regenerated starting material which is followed by the main fraction of the desired 19,21-dihydroxypregna -4,6-diene-3,20-dione-19,21-diacetate.

The product is identical to that according to Example 5,

with m.p. 152-154°C (from methylene chloride-ether).

Example 10■

Tablets containing approx. 50 mg active substance, e.g. 19,21-dihydroxypregna-4,6-diene-3,20-dione or 19,21-diacetate thereof is prepared as follows:

Composition for 1000 tablets:

Manufacturing:

The active substance is mixed with powdered sugar and gum arabic, sieved, granulated using an approx. 35% aqueous sorbitol solution. The granulate is pressed through a sieve, dried, sieved again and mixed well with the other excipients (talc, magnesium stearate, mineral oil and carboxymethylcellulose sodium salt). The mixture is pressed in the usual way into tablets c of 150 mg.

Example 11

Gelatin capsules containing approx. 25 mg active substance, e.g. 19,21-Dihydroxypregna-4,6-diene-3,20-dione or 19,21-diacetate thereof, is prepared as follows:

Composition for 1000 capsules:

The active substance and the lactose are mixed well, torn out and sieved, and the resulting powder is filled in portions of 50 mg each into gelatin capsules.

Example 12

Tablets containing approx. 100 mg of active ingredient, e.g. 19,21-dihydroxy-pregna-4,6-diene-3,20-dione and its 19-acetate or 19,21-diacetate are prepared as follows:

Composition of a tablet:

Production of 10,000 tablets

1 kg of active substance, micronized and 0.5 kg of corn starch are mixed with 0.05 kg of colloidal silicic acid and processed with a solution of 0.05 kg of gelatin in 0.5 kg of distilled water (30°C) to a moist mass. This is pressed through a sieve of 3 mm mesh size and dried for 30 minutes at 45°C (fluid bed dryer). The dry granules are pressed through a sieve of 0.8 mm mesh size, mixed with a previously sieved mixture of 0.8 kg of microcrystalline cellulose and 0.2 kg of sodium carboxymethyl starch, as well as 0.015 kg of magnesium stearate and pressed into tablets of 361.5 mg weight.

Example 13

Dragees containing approx. lOOmg active substance, e.g. 19,21-dihydroxy-pregna-4,6-diene-3,20-dione or its 19-acetate or 19,21-diacetate is prepared as follows:

Composition of a dragon core:

Crafting 50,000 Dragon Cores:

The mixture of 5 kg of active substance, micronized, 4.5 kg of corn starch and 5 kg of tricalcium phosphate is granulated with a solution of 0.75 kg of polyvinylpyrrolidone K 25 in 5 kg of distilled water in the fluidized bed method. 0.1 kg of magnesium stearate and 1.65 kg of sodium carboxymethyl starch are mixed with the granules dried at 45°C and pressed through a sieve of 1 mm mesh size and pressed into curved tablets of 340.0 mg.

Production of 6.6 kg sugar dragées

6 kg of the dragé cores are coated in a dragé ring boiler of 45 cm diameter with a sugar syrup (2 parts sugar and 1 part by weight distilled water), in which 1.5% polyvinylpyrrolidone K 25 and 1% polyethylene glycol 6000 are dissolved, and are suspended 20% talc, up to a weight of 410 mg in portions, in between dried with hot air at approx. 60°C. Sugar syrup (2 parts sugar and 1 part water) is then applied to a final weight of 450 mg in portions. The dragées are then polished with a solution of 2% Carnauba wax in trichloroethylene.

Example 14

Soft gelatin capsules containing 50 mg of active substance ^ e.g. 19,21-dihydroxy-pregna-4,6-diene-3,20-dione or its 19-acetate or 19,21-diacetate. obtained as follows:

Composition of a soft gelatin capsule:

Production of 100,000 soft gelatin capsules

5.0 kg of active substance, micronized, is suspended<;>in a mixture prepared by melting of 0.15 kg of soy lecithin, 0.25 kg of beeswax, 5.4 kg of partially hydrogenated vegetable oil, 11 kg of vegetable oil and brought according to standard procedures in gelatin capsules. The gelatin sleeves consist of approx. 71% gelatin, approx. 28% glycerol (85%) and approx. 1% titanium dioxide, as well as 0.3% p-hydroxybenzoic acid propyl ester. The capsule size is 4 minims (Shape oblong).

Example 15

Film-coated tablets containing 100 mg of active substance,

e.g. 19,21-dihydroxy-pregna-4,6-diene-3,20-dione or its 19-acetate or 19,21-diacetate is prepared as follows:

Composition of a film kite core

Production of 10,000 cores

1.0 kg of active substance, micronized, is mixed in a melt of 0.52 kg of polyethylene glycol (prepared with the addition of 0.05 kg of colloidal silicic acid (specific surface area 200 m 2 /g)) and pressed after cooling through a sieve of 1 mm mesh width.

0.03 kg of powdered, previously sieved stearic acid is mixed with the granulate and pressed into slightly curved tablets of 160 mg.

Production of 30,000 film dragees

4.8 kg of kernels are continuously sprayed under hot air supply of 35°C in a dragé vessel of 45 cm diameter with a solution of hydroxypropylmethylcellulose (viscosity 6 cP, 2% solution in water) in distilled water, in which 2% talc is suspended until 5 mg of varnish is present on each core.

Claims (37)

1. Process for the preparation of 19-oxygenated steroid compounds of the pregnane series with formula I in which R 1 means a hydrogen atom, R 2 means an a-oriented lower alkanoylthio group, or R 1 and R 2 together mean a carbon-carbon bond or an a- or B-oriented methylene residue, R 3 means a free or with a lower alkyl ether or by a lower alkanoyl esterified hydroxymethyl group, a formyl group, a carboxyl group or a lower alkoxycarbonyl group, and R 4 means a hydrogen atom or the acyl residue of a carboxylic acid Ac, as well as by corresponding 1,2-dehydroderivatives and salts of all these compounds, if they contain free carboxyl groups, characterized by that a) in a corresponding derivative with a protected 3- and/or 2O-oxo group, the protecting group or groups are removed while releasing the oxo group or groups, or b) a 17a-isomer compound of formula II 12 3 4 in which R , R , R and R have the above meaning, treated with an enolizing agent, orc) in a corresponding 17-oxo compound of formula III in which R , R and R have the aforementioned meaning, optionally the acylated (2-hydroxyacetyl) side chain is introduced or 1 2 d) for the production of compounds, in which R and R together mean a C-C bond, and of their 1,2-dehydroderivatives are a corresponding 6,7-saturated out-aanac;c;f nf f mf^ rl frnrme*~\ TV in which R 3 and R 4 have the above meaning, resp. a 1,2-dehydro derivative, or a 3-enol ether from the 1,2-saturated compounds, dehydrogenated in the 6,7-position and possibly simultaneously also in the 1,2-position, the possibly present 3-ether group being cleaved or for the production of a compound of formula I, in which 12 3 R together with R means a C-C bond, R means a lower alkanoyl-oxymethyl group and R 4 means an acyl group Ac, react a corresponding to 63,19-epoxide of formula V wherein R 4 has the above meaning, with an acylating agent derived from a lower alkanoic acid in an anhydrous medium in the presence of a strongly acidic catalyst, and if desired for the preparation of compounds of formula I, in which R <1> means et hydrogen atom and R 2 means an α-oriented lower alkanoylthio group is added to a formed corresponding compound of formula I, wherein R 1 and R 2 together mean a C-C bond, a lower alkanethioic acid, or 1 2 for the preparation of compounds of formula I, in which R and R together mean a methylene group, are added to a formed corresponding compound of formula I, in which R 1 and R 2 together mean a C-C bond, the methylene group, and if desired is released in a formed final substance an esterified hydroxyl group in the residue R 3 and/or OR <4> hydrolytically or a free hydroxyl group is esterified and/or if desired the 103-hydroxymethyl group is oxidized to the formyl group, or to the carboxyl group or the formyl group to the carboxyl group and/or the carboxyl group is esterified and/or an esterified carboxyl group is released and/or if desired a formed 1,2-saturated end product is dehydrogenated in the 1,2 position and/or if desired a formed end product with a free carboxyl group is converted by treatment with a base into a salt thereof or such a salt is transferred by acidification in the corresponding acid. 2. Method according to claim 1, characterized in that a) in a corresponding derivative with protected 3- and/or 20-oxo groups, the protecting group or groups are removed while releasing the oxo group or groups, or b) for the preparation of compounds, in which R 1 and R <2> together mean a C-C bond, as well as of their 1,2-dehydroderivatives becomes a corresponding 6,7-saturated starting material with formula IV 3 4 in which R and R have the above meaning, resp. a 1,2-dehydro derivative, or a 3-enoleter of the 1,2-saturated compound, dehydrogenated in the 6,7-position and possibly simultaneously also in the 1,2-position, with the possibly present 3-ether group being cleaved and to produce a compound of formula I, in which R means a hydrogen atom and R 2 an α-oriented lower alkanoylthio group is assigned to a formed corresponding compound of formula I, in which R 1 and R 2 together form a C-C bond, a lower alkanethioic acid, or c) for the preparation of compounds of formula I, in which R 1 and R 2 together mean a methylene group, are added to a formed corresponding compound of formula I, in which R and R <z> together mean a C-C bond, the methylene group, and if desired in a formed final substance, an esterified hydroxyl group is released hydrolytically in the residue R <3> and/or OR <4> , or a free hydroxyl group is esterified, and/or if desired, the 10 6-hydroxymethyl group is oxidized to the carboxyl group and/or the carboxyl residue is esterified and/or a esterified carboxyl residue is released, and/or if desired, a formed 1,2-saturated end product is hydrogenated in the 1,2 position and/or if desired, a formed end product with a free carboxyl group is converted by treatment with a base into a salt thereof, or such a salt is transferred by acidification in the corresponding acid. 3. Method according to claim 1, characterized in that a strong base is used as enolizing agent. 4. Method according to claim 1, characterized in that an acid is used as an enolizing agent. 5. Method according to claim 1, characterized in that a corresponding 173-cyano compound is used as an intermediate for introducing the side chain. 6. Process according to claim 1, characterized in that a corresponding 173-carboxylic acid is used as an intermediate when introducing the side chain. 7. Method according to claim 6, characterized in that one converts the acid in the acid chloride, reacts this with diazomethane, and transfers the formed 21-diazo-20-ketone with the aid of an acid AcOH in the 20-oxo-21-acyloxy end substance. 8. Process according to claim 1, characterized in that a corresponding 17 3-carboxaldehyde is used as an intermediate for introducing the side chain, which is treated with a reagent that arises from formaldehyde-dimethylmercaptal-S-oxide during metallation with an organo-alkali metal compound and acid hydrolyzes the 2o-hydroxy-21-aldehyde derivative formed. 9. Method according to one of claims 1 and 8, characterized in that one works under a temporary protection of the 3-oxo group. 10. Method according to claim 9, characterized in that the 3-oxo group is protected as the 3,3-ethylene dithio group. 11. Method according to claim 2, characterized in that one hydrogenates by treatment with a de-hydrogenating quinone. 12. Method according to claim 2, characterized in that a 3-enol ether is dehydrogenated by the action of manganese dioxide. 13. Method according to claim 2, characterized in that the methylene group is added by reacting a corresponding 6,7-dehydro compound with dimethyloxofulfonium methylide. 14. Process according to one of claims 1-13, characterized in that by suitable choice of starting materials and process steps, compounds of formula Ia are prepared in which R 1 means a hydrogen atom and R 7 an a-oriented lower alk-1 2 noylthio group, or R and R together mean a carbon-carbon bond or an a- or 3-oriented methylene residue, R a3 means a free or with a lower alkyl etherified or with a lower alkanoyl esterified hydroxymethyl group, a carboxyl group or a lower alkoxycarbonyl group and R <4> means a hydrogen atom or the acyl residue of a carboxylic acid Ac, or their 1,2-dehydro derivatives or salts rather than all of these compounds. 15. Process according to claim 14, characterized in that compounds of the formula Ia stated in claim 14 are prepared with the precaution that in 1,2-saturated compounds, in which R<1> and R^ mean a C-C bond, and R^ means an acyl radical Ac, R c3l means a hydroxymethyl group etherified with a lower alkyl or esterified with a lower alkanoyl group, a carboxyl group or a lower alkoxycarbonyl group and in 1,2-saturated compounds, 12 4 in which R and R mean a C-C bond and R means hydrogen atom, Ra 3 means a free or preferably one with a lower alkyl etherified or with a different from acetyl lower alkanoyl esterified hydroxymethyl group, a carboxyl group or a lower alkoxycarbonyl group. 16.. Method according to one of claims 1-15, characterized in that one starts from an arbitrary process step as an intermediate of a compound and carries out the missing process steps. 17. Method according to one of claims 1-16, characterized in that a starting substance is formed under reaction conditions or is used in the form of a derivative thereof. 18. The methods mentioned in examples 1-9. 19. Method according to one of claims 1-13, characterized in that 19-oxy- generated steroid compounds of the pregnane series of formula Ia in which R means a hydrogen atom and R^ an a-oriented lower alka-1 2 noylthio group, or R and R together mean a carbon-carbon bond or an ot- or 3-oriented methylene residue, R<3> means a free or etherified with a lower alkyl or esterified with a lower alkanoyl hydroxymethyl group, a carboxyl group, or a lower alkoxycarbonyl group, R <4> means a hydrogen atom or the acyl residue of a carboxylic acid Ac, as well as 1,2-dehydroderivatives thereof and salts of all corresponding compounds with free carboxyl groups. 20. Method according to claim 19, characterized in that pharmaceutically usable salts of compounds according to claim 19 are produced. 21. Method according to claim 19, characterized in that potassium salts are produced from compounds according to claim 19. 22. Process according to claim 19, characterized in that compounds are prepared, where R& 3 means a free or lower alkanoyl esterified hydroxymethyl group and R<4> means hydrogen or acyl. 23. Method according to claim 19, characterized in that compounds of formula Ia are prepared, 1 2 12 in which R means hydrogen and R means α-acetylthio or R and R together means a 6-oriented methylene group, R 3 means hydroxymethyl, a4 is lower alkanoyloxymethyl or lower alkoxycarbonyl and R means hydrogen or lower alkanoyl. 24. Method according to claim 1, charac- see 2 that compounds of formula IA are produced wherein 1 means a lower alkanoyl residue and RA 2 means an acyl residue Ac. 25. Method according to claim 1, characterized in that compounds are prepared with the formula IA specified in claim 24, in which R 1 means a hydrogen atom. 26. Method according to claim 1, characterized in that 19,21-dehydroxy-pregna-4,6-diene-3,20-dione is produced. 27. Method according to claim 1, characterized in that 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19,21-diacetate is produced. 28. Method according to claim 1, characterized in that 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate is produced. 29. Process according to claim 1, characterized in that 19,21 dihydroxy-pregna-4,6-diene-3,20-dione-21-acetate is produced. ■^0 au an forhindpl co mori in which R means a hydrogen atom and R means an α-oriented lower alkanoylthio group, or R 1 and R 2 together mean a carbon-carbon bond or an α- or 3-oriented methylene residue, R 3 means a free or at a lower alkyl etherified or at for treatment of disease states caused by Hyperaldosteronism in humans and other warm-blooded animals. 31. Pharmaceutical compositions containing as active substance at least one compound of formula I in which R 1 means a hydrogen atom and R 2 means an α-oriented lower alkanoylthio group or R 1 and R 2 together mean a carbon-carbon bond or an α- or 3-oriented methylene residue, R 3 means a free or with a lower alkyl etherified or with a lower alkanoyl esterified hydroxymethyl group, a formyl group, a carboxyl group or a lower alkoxycarbonyl group and R <4> means a hydrogen atom or the acyl residue of a carboxylic acid Ac, or a corresponding 1,2-dehydro derivative or a salt of such a compound, if it contains free carboxyl groups, together with at least one pharmaceutically usable carrier. 32. Pharmaceutical compositions according to claim 31, containing at least one of the compounds defined in claims 19-29. 33. Pharmaceutical compositions according to claim 31, containing 19,21-dihydroxy-pregna-4,6-diene-3,20-dione-19-acetate or -21-acetate. 34. Medicine in the form of dosage units consisting mainly of a pharmaceutical composition according to one of claims 31-33. 35. Medicine according to claim 34, in solid or semi-solid form for oral administration. 36. Medicine according to claim 35, containing 10-100mg of the active substance per dosage unit. 37. Therapeutic method for combating disease states associated with hyperaldosteronism in humans and other warm-blooded animals, characterized by administering a therapeutically effective dose of at least one compound share from the pregnan series with formula I in which R 1 means a hydrogen atom and R 2 means an a"-oriented lower alkanoylthio group, or R 1 and R 2 together mean' a carbon-carbon bond or an a- or 3-oriented methylene residue and R 3 means a free or with a lower alkyl etherified or with a lower alkanoyl esterified hydroxymethyl group, formyl group, a carboxyl group or a lower alkoxycarbonyl group, and R4 means a hydrogen atom or the acyl residue of a carboxylic acid Ac, or a corresponding 1,2-dehydro derivative or a salt of such a compound, if it contains free carboxyl groups alone or in the form of a medicine.